Certain (alpha-indenyl-benzyl)-pyridines



United States Patent Delaware No Drawing. Filed Aug. 17, 1962, Ser. No. 217,518 14- Ciaims. (Cl. zen-29s The present invention relates to pyridine compounds. Primarily, it concerns compounds of the formula:

in which Py represents a pyridyl radical, ind stands for a Z-(tertiary amino-lower alkyl) -3-indenyl radical, Ph represents a monocyclic carbocylclic aryl group, and R stands primarily for hydrogen, as well as for lower alkyl, salts or quaternary ammonium derivatives of such compounds, as well as process for the preparation of such compounds.

A pyridyl-radical stands primarily for Z-pyridyl, but may also represent 4-pyridyl or 3-pyridyl and the like; a pyridyl radical is preferably unsubstituted or may be substituted by lower alkyl, e.g. methyl, ethyl and the like, or any other suitable substituent, such as, for example, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. iiuoro, chloro, bromo and the like, or any other suitable functional group.

[The lower alkyl portion of the tertiary amino-lower alkyl group of the 2-( tertiary amino-lower 'alkyl)-3-indenyl radical 1nd may be represented by lower alkylene containing from one to seven, preferably from two to three, carbon atoms; such radicals are, for example, -1, 2 ethylene, l-methyl-l,2-ethylene, Z-methyl-LZ-ethylene or 1,3-propylene, as well as methylene, -1,1-ethylene, l- -methyll,3-propylene,1,4 butylene, lamethyl 1,4 butylene, 1,5-pentylene and the like.

The tertiary amino group of the Z-( terti-ary aminolower alkyl)-3-indenyl substituent Ind may represent, for example, an N,N-di-hydrocarbon-amino group, such as N ,N-di-lower alkyl-amino, in which lower alkyl has from one to four carbon atoms, e.g. 'N,N-dimethylamino, N- methyl-N-ethylamino, lLN-diethylamino, N,N-di-n-propyl-arnino, N,N-di-isopropyl-amino, N,N-di-n-bu-tyl-ami no, N,N-di-isobutyl-amino and the like, N-cycloalkyl-N- lower alkyl amino, in which cycloalkyl has from five to seven ring carbon atoms, and lower alkyl has from one to four carbon atoms, e.g. N-cyclopentyl-N-methyLamino, N-cyclohexyl-N-rnethyl-amino, N-CYOlOhEXYl-N-BtllYlamino and the like, or N-lower alkyl-N-phenyl-lower alkyl-amino, in which lower alkyl has from one to tour carbon atoms, e.g. N-benzyl-Nmethyl-amino,N-benzyl-N- ethyl amino, N-rnethyl N (l-phenylethyl)-amino, N- methyl-N-(2-phenylethyl)-amin0 and the like, or any other N,N-di-hydrocarbon-amino group. The substituents of the nitrogen atom, particularly lower alkyl, may also have functional groups, such as hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and the like, lower *alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or any other suitable group as substituents. N,N-di-hydrocarbon-amino groups, in which the hydrocarbon radical contains functional groups as substituents are, for example, N-hydroxy-lower *alkyl-N-lower alkyl-amino, e.g. N-(Z-hydroxy-ethyl)aN-methyl-amino and the like, N,N-di-hydroxy-l-ower ralkyl amino, e.g. N,N-di- (2-hydroxy-ethyl)- amino and the like.

The tertiary amino group may also be represented by l-N,N-. alkylene-imino or by l-N,N-aza=alkylene-imino groups, in which the aLkylene portions have from four to six carbon atoms, as well as by l-N,N-oXa-a-lkylene-imino and by l-N,N-thia=a'lkylene-imino, in which alkylene has preferably four carbon atoms. Together with the nitrogen atom such alkylene, aza-alkylene, oxa-alkylene or thia-alkylene radicals represent, for example, 'l-N,N- :alkylene-imino, in which alkylene has from four to six carbon atoms, such as l-pyrrolidino radicals, e.g. l-pyrrolidino, Z-methyhhpyrrolidino and the like, l-piperi-dino radicals, e.g. 'l-piperid'ino, 2-methyl l-piperidino, 4-methyl l piperidino, Z-hydroxy l piperidin-o, =3-acet-oxy-lpiperidino, 3-hydroXymethyl-l-piperidino, 3-acetoxy-lpiperidino, 3-hydroxymethyl-l-piperidino and. the like, l N,N-l,6-hexylene-imino and the like, l-N,N-(iaza-alkylene)-imino, in which alkylene has from four to six carbon atoms, particularly 1-N,-N-('N-lower alky-laza'alkylene)-imino, in which alkylene has from four to six carbon atoms, such as 1-N,N (3-aza-l,5-pentylene)-irnino, particularly l-N,N-( 3-aza-3-lower .alkyll,5pen-tylene) -imino, e.g. 4-met-hyl-l-piperazino, 4-ethy l-piperazino and the like, as well as 4-hydroxyethyl-lpiperazino, 4-.acetoxyethyl-l-piper-azino and the like, l-N,N-(3 aza-l,6- hexylene)-imino, e.g. l-N,N-(3-aza-3-methyl-1,6-hexyl e-neyimino and the like, or l-N,N-(4-aza-1,7-heptamethylene)-imino, particularly l-N,N-(4-aza-4-lower alkyl- 1,7-heptamethylene)-imino, e.g. l-\ ,T-I-'(4-aza-4-methyl- 1,7-heptamethylene)-imino and the like, lN,N-(3-oxal,5-pentylene)-imino, e.g. 4-morpholino and the like, 1- N,N-(3-thia1l,5-pentylene)-imino, e.g. 4-thiamorpholino and the like. 7

The l-position of the Z-(tertiary amino-lower ulkyl)-3- indenyl substituent is prefer-ably unsubstituted, or if substituted, contains primarily a hydrocarbon radical, particularly lower \alkyl, e.g. methyl, ethyl and the like, or mono-cyclic carbocyclic ary-l-lower alkyl, e.g. benzyl and the like.

The siX-membered carbocyclic aryl portion of the 2- (tertiary amino-lower alkyl)-3-indenyl substituent is preferably unsubstituted or may contain one or more than one substituent, which may be located in any of the four positions available for substitution; whenever more than one substituent is present, these may be of the same or of different nature. Such substituents may be, for example, lower alkyl, e.g. methyl, ethyl and the like, halogeno-lower alkyl, e.g. trifiuoromethyl, etherified hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, esterified hydroxyl, such as lower alkoxy-carbonylox e.g. methoXy-carbonyloxy, ethoxy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetyloxy, propionyloxy and the like, or halogeno, e.g. fluoro, chloro, brorno and the like, acyl, such as lower alkanoyl, e.g. acetyl, propionyl and the like, etherified mercapto, such as lower alkylmercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, for example, unsubstituted amino, N- mono-substituted amino, such as N-lower alkyl-amino, e.g. N-methylamino and the like, or, preferably, N,N- disubstituted amino, for example, N,N-di-lower alkylamino, e.g. N,N-dimethylamino and the like. The sixmernbered carbocyclic aryl portion of the 2-(tertiary amino-lower alkyl)-3-indenyl substituent Ind may, therefore, be represented, for example, by an unsubstituted, a lower alkyl-substituted, a halogeno-lower alkyl-substituted, a lower alkoXy-substituted, a lower alkylenedioxysubstituted, a lower alkoxy-caibonyloxy-substituted, a

' amino groups present.

pounds are those with reactive esters of alcoholsw ith 3 lower alkanoyloXy-substituted, ahalogeno-substituted, a lower alkanoyl-substituted, a lower alkyl-mercapto-substituted, a nitro-substituted, an amino-substituted, an N- lower alkyl-amino-substituted or an N,N-di-lower alkylamino-substituted six-membered carbocyclic aryl portion.

above formula represents phenhl, or phenyl-substituted by one or more than one of the same or of difierent substituents which may be attached'to any of the positions available for substitution. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl, isopropyl, n-butyl and the like, lower alkoXy, e.g. methoxy, ethoxy, 'n-propyloxy, isopropyloxy and the like, halogeno, e.g. 'fluoro, chloro, bromo and the like, trifluoromethyl, nitro, amino, such as N,N-di-l0wer alkyl-amino, e.g. N,N-di methylamino, N,N-diethylamino and the like, or any other suitable g'roup. A substituted phenyl group may, therefore, be represented by (lower alkyl)-phenyl, e.g. 3-methylphenyl, 4-isopropyl-phenyl and the like, (lower alkoxy) phenyl, e.g. 4-methoXy-phenyl, '3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, Z-ethoxy-phenyl and the like, (halogeno)-phenyl, e;g.' 4-fluoro-phenyl, 3-chloro-phenyl, 2,5-dichloro-phe nyl, 4-bromo-phenyl and the like, (trifluorornethyD-phenyl, e.g. 4-trifluoromethyl-phenyl and the like, (nitro)-phenyl, e.g. 4-nitro-phenyl and the like, (N,N-di-lower alkyl-amino)-phenyl, e.g. 3-N,N-dimethylamino-phenyl and the like, or any other suitably substituted phenyl group. 7

Q The group R in the above formula represents primarily hydrogen, but it may also stand for lower alkyl, e.g. methyl, ethyl, isopropyl and the like.

a Salts of the compounds of this invention are particularly acid addition salts, such as the pharmaceutically acceptable, non-toxic addition salts with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, thiocyanic, sulfuric, phosphoric acids and'the like, or with organic acids, e.g. acetic, propionic, maleic, hydroXy-m-aleic, furnariqmalic; tartaric, citric, methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, ethane 1,2-disulfonic, p-toluene sulfonic acid and the like. Other acid addition salts may be used as intermediates, which may be employed, for example, in the purification of the free compounds or in the preparationof other salts, or for the purpose of identification and characterization. Salts which are primarily used for identification purposes are particularly those with acidic organic nitro compounds, e.g. picric, picrolonic, fiavianic acid, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like. Monoor poly-salts may be formed, depending on the procedure used for the preparation of the salts.

Quaternary ammonium compounds of the above compounds may be either monoor poly-quaternary ammonium compounds, depending on the conditions of the quaternization reaction and/or the number of tertiary Quaternary ammonium' comacids, particularly the lower alkyl quaternaryammonium' halides, sulfates, sulfonates and the like, such'as those formed with lower alkyl halides, e.g. methylxchloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl iodide, isopropyl bromide, isopropyl iodide, n-butyl bromide and the like, di-lower alkyl'sulfates, e.g. dimethyl sulfate, diethyl sulfate'and the like, lower alkyl lower'alkane sufonates; e.g.' methyl methane sulfonate, methyl ethane sulfonate, ethyl methane sulfonate, ethyl ethane sulfonate, n-propyl methane sulfonate and the like, lower alkyl hydroxy-lower alkane sulfonatesyeg. methyl Z-hydroxyethane sulfonate and the like, lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl p-toluene sulfonate and the like, or themonocyclic carbocyclic aryl-lower alkyl,

,7 especially the phenyl-lower alkyl, quaternary ammonium The monocyclic carbocyclic aryl radical Ph in the V halides, sulfates, sulfonates formed with monocyclic carbocyclic aryl halides, especi-' ally phenyl-lower alkyl halides, e.g. benzyl chloride, benzyl bromide, benzyl iodide, 2-phenylethyl chloride, '2-phenylethyl bromide and the like, monocyclic carbo'cyclic aryllower alkyl lower alkane sulfonates, particularly phenyllower alkyl lower alkane sulfonates, e.g. benzyl methane sulfona'te, benzyl ethane sulfonate, 2-phenylethyl methane sulfonate and the like, monocyclic carbocyclic aryl-lower alkyl monocyclic carbocyclic aryl sulfonates, such as phen yl-lower 1 alkyl monocyclic carbocyclic aryl 'sulfonates,

rivatives;

, Also included as quaternary ammonium compounds are the corresponding quaternary'ammonium hydroxides, and other quaternary ammonium'saltswith acids, particularly with the other acids'mentioned hereinabove.

The compounds of this invention may be obtained as mixtures of isomers, e.g. racernates and the like, the sep-' aration arid resolution of which'will b e discussed and illustrated hereinbelow;

The compounds of this invention have antispasmodic: properties and can be used accordingly, for example, to

relieve spastic conditionsof smooth muscle tissue, for example, spastic conditions of the gastrointestinaltract,

as caused by'mental tension, hyperactivity duefto food poisoning and'the like, or spastic conditions of other smooth muscle tissues, e.g. dismenorrhea and the like.

. Particular advantages of the pharmacologically' active compounds of this invention are their oral activities and. the absence of any other pharmacological effects andside:

reactions. 7 V

The free bases and the salts thereof, although they, too,

'- have antispasmodic etfectsycan also be used asintermediates in the manufacture of the quaternary ammonium scribed hereinbelow. 7

Non-quaternary ammonium compounds are those having the formula I derivatives; their conversion into the latter will be dein which is lower alkylene, stands for N,l I-di-lower alkyl-amino, N-cycloalkyl-N-low'er alkyl-amino, in which cycloalkyl has from five to seven ring carbon atoms; N- lower alkyl-N-phenyl-lower alkyl-amino, l-N,N-alkyleneimino, in which alkylene has from four to six carbonatoms, 4-morpholino or 'l-N,N (N-lowe r alkyl-aza alkylene)-imino, in which alkylene has from'four to 'six carbon 7 atoms, particularly 4-lower alkyl-l-piperaz'ino, R is jhydrogen, lower alkyl, trifiuoromethyl, lower alkoxy; halo: geno, lower alkanoyl or N,N-di.-lower alkyl-amino, R stands for hydrogenor lower alkyl, and .Ph is phenyl, (lower alkyl -phenyl, (lower alkoxy) -phenyl, (halogeno a phenyl or (trifluoromethyD-phenyl, or acid addition salts thereof. T hese compounds, which have :antis-pasmodic i properties of their own and may be used accordingly,

mayalso be converted into the quaternary ammoniumv derivatives according to the procedure described hereinv below. Quaternary ammonium compounds exerting strong antispasmodic'effects are'espec ially'the mono-lower.

alkyl, bis-lower alkyl, poly-lower alkyl, mono-phenyl-j and thelike, such as those;

especially 7 alkyl quaternary ammonium halides, sulfates or sulfonates of the compounds having the formula Ph'CH R1 C-AAm in which A is lower alkylene, having from two to three carbon atoms, and A111 represents N,Ndi-lower alkylamino, acid addition salts thereof and the lower alkyl n quaternary ammonium halidesthereof.

The compounds of this invention may be used in the form of compositions suitable for enteral or parenteral use, which contain the new compounds in admixture with an organic or inorganic, solid or liquid'car-rier. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier used for such prepartions. The latter may be prepared according to methods known in the art and may be in solid form, for example, as capsules, tablets, drages and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring, flavoring agents and the like, salts for varying the osmotic pressure, bufiers, etc. They may also contain, in combination, other useful substances.

The compounds of this invention may be prepared, for example, by reacting an alkali metal compound of an a.- (monocyclic carbocyclic aryl)-lower alkyl-pyridine compound of the formula in which Py, Ph and R have the above-given meaning, with a 2-(tertiary amino-lower alkyl)-indan-l-one, and, if necessary, splitting oil the elements of water from a compound containing a l-hydroxy-Z-(tertiary amino-lower alkyl)-l-indanyl substituent by dehydration, and, it desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into a salt or a quaternary ammonium compound thereof, and/ or, if desired, converting a quaternary ammonium compound into another quaternary ammonium compound, and/or, if desired, separating a mixture of isomeric compounds into single isomers.

The alkali metal in an alkali metal compound of an a-(monocyclic carbocyclic aryl)-lower alkyl-pyridine is primarily lithium, but may also be another alkali metal, e.g. sodium and the like.

The reaction is carried out according to known methods, especially in the presence of an inert solvent, for example, a hydrocarbon, such as an aliphatic hydrocarbon, e.g.

pentane, hexane and the like, or an aromatic hydrocarbon, e.g. benzene, toluene, xylene and the like, or an ether, such as di-lower alkyl ether, e.g. diethyl ether, diisopropyl ether and the like, or a cyclic ether, e.g. tetrahydrofuran, p-dioxane and the like, or any other suitable diluent or solvent mixture. The reaction may be carried out while cooling, at room temperature or at an elevated temperature, preferably the atmosphere of an inert gas, e.g. nitrogen.

The above-mentioned alkali metal compound of an CC-(IROHOCYCHC carbocyclic aryl)-lower alkyl-pyridine compound, particularly a lithium derivative, may be formed by reacting an e-(monocyclic carbocyclic ary1)- lower alkyl-pyridine with an aryl metal compound, such as a monocyclic carbocyclic aryl alkali metal compound, e.g. phenyl lithium and the like, or with an aliphatic hydrocarbon alkali metal compound, particularly a lower alkyl lithium derivative, e.g. n-butyl lithium and the like. Such reaction is carried out in the presence of an inert solvent, for example, a lower aliphatic hydrocarbon, e.g. pentane, hexane and the .ike, an aromatic hydrocarbon, e.g. benzene, toluene, xylene and the like, or an ether, such as a di-lower alkyl ether, e.g. diethyl ether, di-isopropyl ether and the like, or a cyclic ether, e.g. tetrahydrofuran, p-dloxane and the like, or any other suitable diluent or solvent mixture, preferably in the atmosphere of an inert gas, e.g. nitrogen.

The preparation of the a-(monocyclic carbocyclic aryD-lower all'yl-pyridine alkali metal, particularly lithium, reagent may be modified. Thus, it may also be obtained by treating with lithium an ether formed, for ex ample, by a lower alkanol and an a-hydrox -u-(monocyclic carbocyclic aryl)-lower alkyl-pyridine; advantageously, such reaction occurs by using a diluted solution of the ether reagent in an inert solvent, particularly in tetrahydroiuran. The resulting solution of the lithium re agent is then reacted with the Z-(tertiary amino-lower alkyl)-indan-l-one compound according to the previouslydescribed procedure.

The above reaction of the Z-(tertiary amino-lower alkyl)-indan-l-one compound with the alkali metal reagent of an a-(HIOILOCYCHC carbocyclic aryl)-lower alkylpyridine may furnish directly the desired compound having a 2- tertiary amino-lower alkyl)-3-indenyl substituent, since an intermediarily formed compound having a lhydroxy-Z-(tertiary amino-lower alkyl)-l-indanyl substituent may be dehydrated under the conditions of the reaction and yield directly the desired 2-(tertiary aminolower alkyl)-3-indenyl substituent. Particularly, direct dehydration takes place if, at any stage of the isolation procedure of the reaction product, acidic conditions are prevailing. if necessary, dehydration of a resulting compound having a l-hydroxy-Z-(tertiary amino-lower alkyl)- l-indanyl substituent may be achieved and completed, for example, by treatment with an acidic reagent, for example, with a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like. These acids may be use in the presence of water and/ or an organic solvent, such as, for example, glacial acetic acid and the like. Dehydration may also be accomplished by treatment with an organic acid reagent, such as an organic carboxylic acid or an organic sulfonic acid, e.g. oxalic, p-toluene sulfonic acid and the like, or an organic carboxycil acid anhydride, e.g. acetic acid anhydride and the like, or with an inorganic or organic acid halide, e.g. phosphorous oxyclloride, acetyl chloride and the like, if desired, in an organic base, e.g. pyridine and the like, it necessary, while heating. Resulting compounds containing a l-hydroyx-Z-(tertiary amino-lower alkyl)-1-indanyl substituent may also lose Water at an elevated temperature without the presence of a specific dehydrating agent.

The Z-(tertiary amino-lower alkyD-indan-l-one com pounds used as the intermediates in the above reaction are known, or, if new, may be prepared according to methods used for the manufacture of known analogs. For

'2 example, an u-benZyl-malonic acid ester, such as a'lower alkyl, e.g. methyl, ethyl and the like, ester, as Well asa suitable heterocyclic, eg. Z-tetrahydropyrariyl and' the like, ester, in which thebenzyl portion may be unsubsti- ,tuted or substituted as 'outlinedhereinabove, is treated with a reactive ester formed by'a tertiary amino-lower alkanol, inwhich the tertiary amino group is separated from the hydroxyl group by at least two carbon atoms, and a strong inorganic acid, such as, for example, a mineralacid, e.g. hydrochloric, hydrobromic,,hydriodic, sulfuric acid and the like. The reaction produces an abenzyl-a-(tertiary amino-lower alkyl)-malonic acid ester,

in which the'tertiary amino group is separated from the V a-carbon atom by at least'two carbon atoms. This condensation may preferably be carried out in the presence of a base, such as an alkali metal lower alkanolate, e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanolate, isopropanolate or, tertiary butanolate and the like. 'The'resulting malonic acid ester may then be cyclized to the 2-(tertiary amino-lower alkyll-indan b one, lin'which the tertiary amino group is separated from the indane' nucleus by at least tworcarbon atoms. The

' 'tion may be carried out, for example, by treatment with a strong Lewis acid, such as a strong mineral acid, e.g.

anhydrous hydrofluoric, sulfuric,*phosphoric acid (preferably in the 'form of polyphosphoric' acid), boron tri fluoride (primarily in the form of its etherate), aluminum chloride and the like.

" The Z-(tertiary amino-methyl)-indan 1-ones may be prepared by another route, for example, by reacting an indan-l-one with a secondary amine or a salt thereof in the presence of formaldehyde according to the Mannich procedure Secondary amines are those which furnish the N,N -disub'stituted amino groups described 'hereiubefore; salts of such amines are particularly inorganic acid.

addition salts, for example, salts with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric acid and the like. The formaldehyde may housed in the form of'a solu-' tion, e.g. aqueous formaldehyde, as a polymer, e.g. trioxymethylene, 'paraformaldehyde and the like, or as an 7 'acetal with a lower alkanol, e.g. dimethoxy-methane, di-

ethoxyethane and the like. The reaction is advantageously performed in the presence of a solvent, for example, a lower alkanol, e.g. methanol, ethanol and the like, or an aqueous mimure thereof, and/or inthe presence of an acid, for example, a mineral acid, e.g. hydrochloric, sulfuric acid and the like, especially when the formaldehyde'is employed in the form of a polymer or an acetal thereof. 'The reaction maybe completed'by heating, and the resulting Z-(tertiary amino-methyl)-indan-laone may be isolated as the free base or as an acid addition salt thereof.

A salt resulting from the above procedure may be converted into the free base, for example, by reacting it with an alkaline reagent, such as aqueous alkali metal hydroxide, 'e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, aqueous alkali metal carbonate, 'elg. sodium or potassium carbonate or hydrogen car- A free base'may be converted into 'an acid addition salt by reacting the'former with one 'of the organic acids mentioned hereinbefore. The salt-forming reaction is carried out, for example, by treating a solution of the free base in a solvent or solvent mixture with the adder 21 solution thereof and isolating the desired salt. The. salts may also be obtained as thehydrate's or may contain solvent of crystallization; monoor poly-salts may be formed depending on the conditions used for the preparation of the salts; 7

The quaternary ammonium compounds are prepared according to known methods, for. example, by treating the free compound with one of the reactive esters formed by an alcohol and an acid, such as one of those mentioned above. Quaternization may be performed in the absence" or presenceof a solvent, under cooling, at 'roorr rtempera-l ture 'or at an elevated temperature,' at atmospheric pressure or in a closed vesselunder pressure, and, if desired, in the atmosphere of an inert gas, e.g. pitrogen. Suitable diluents are more especially lower alkanols, e;g.jmethanol,

ethanol, n-propanol, isopropanol, tertiary butanol, 'npentanol and the like, lower alkanones, e.g. acetone, ethyl methyl ketone and the like, organic acid amides, e.g. formamide, .N,N-dimethylformamide and the like, aliphatic hydrocarbons, e.g. pentane, hexane and' the like,

halogenated hydrocarbons, e.g. methylene chloride,'e thyl ene chloride and the like, monocyclic'carbocyclic aryl hydrocarbon, e,g. benzene, -toluene and the like, or any j other suitable solvent,

A resulting quaternaryamrnonium compound may be} converted into the corresponding quaternary ammonium hydroxide, for example, by reacting a quaternary ammoniuni halide with silver oxide, or a quarternary ammomum sulfate with barium hydroxide, or by treating a' quaternary ammonium salt with a hydroxyl io'nfexcha'nge preparation, or by electrodialysis. From a resulting quaternary ammonium hydroxide there maybe obtained a quaternary ammonium salt by reacting the base with acid,

for example, with one ofthe acidsused in mg reaction.

the salt-form- A quarternary ammonium compound may also be con-.

verted directly into another quaternary ammonium salt I 2 without the formation of an intermediate quaternary amrnonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly'prepared silyer, ch10: I'ldelO yield the quaternary ammonium t chloride; or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment of a'solution of the former with hydrogen chloride, or the anion of a quaternary ammonium compound, for example, a halide, such as the iodide, may be exchanged for another anion, for example, another halide, such as the chloride, by treatment with a suitable anion exchange preparation, such as, for example, with Amberlite IRA-400 (as described.

in US. Patent No. 2,591,573).

Quaternary ammonium compounds may be isolatedas hydrate'or may contain solvent of crystallization; (le

pending on the conditions for their formation monoor poly-quaternary ammonium compounds may be'formed.

Mixtures of isomers of resulting compounds maybe separated into the single isomers. For example, a mixture of racemates maybe separated into individual .racesolution of the free base of a racemateta d,l-compo,und) f in a suitable solvent or solvent mixture is added one of the optically active forms of an acid, containing an asym metric carbon atoms, or a solution thereof. Especially useful as optically active forms of salt-forming acids, having an asymmetric carbon atom are the d-tartaric acid (L-tartaric acid) and the l-tartaric acid (D-tartaric acid); the optically active forms of dibenzoyl tartaric, di-ptoluyl-tartaric, malic, mandelic, ltl-camphor sulfonic acid, quinic acid and the like, may also be used. Salts which are formed by the optically active forms of the base with the optically active form of the acid may then be isolated, primarily on the basis of their different solubilities. The free and optically active base may be obtained from a resulting salt according to the method outlined hereinbefore, and, if desired, converted into an acid addition salt or a quaternary ammonium-compound as shown above. The optically active forms may also be isolated by biochemical methods.

If desired, optically active forms of compounds of this invention, or of salts thereof, may be reconverted into racemates. Racemization may be achieved according to known racemization procedures, for example, by heating of the optically active free base, either with an alkaline reagent, such as, for example, aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or an alkali metal, e.g. sodium, potassium and the like, or an alkali metal amide, e.g. sodium amide, potassium amide, and the like, in liquid ammonia, or any other suitable alkaline reagent, or with an acid reagent, such as an inorganic acid, for example, a mineral acid, e.g. hydrochloric, sulfuric acid and the like, or a strong organic acid, for example, a strong organic sulfonic acid, e.g. p-toluene sulfonic acid and the like. Racemization of one of the optically active forms may be advantageously employed to enhance the yield in the formation of the other optically active form which has the opposite rotation; a racemate resulting from such a racemization procedure can then be recycled into the resolution procedure.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outlined hereinbefore.

in the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No. 144,820, filed October 13, 1961, which in turn is a continuation-inpart application of my application Serial No. 83,618, filed January 19, 1961, both now abandoned.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A solution of phenyl lithium (prepared by reacting 1.75 g. of lithium and 20 g. of bromohenzene in 109 ml. of diethyl ether) is slowly added over several hours to a solution of Z-benzyl-pyridine in 50 ml. of anhydrous diethyl ether while stirring and maintaining an atmosphere of dry nitrogen. After standing at room temperature for about four hours, a solution of 10 g. of 2-(N,N- dimethylaminoethyl)-indan-l-one in 50 ml. of anhydrous ether is added dropwise While stirring. The reaction mixture is allowed to stand overnight at room temperature and is then treated with water. The organic material is extracted with an excess of 3N aqueous hydrochloric acid, and the acid extract is heated on the steam bath for thirty minutes, then cooled and basiiied with ammonia. The organic material is extracted with diethyl ether, the solvent is evaporated, and thercsidue is dis- 19 tilled to yield the Z-{a-[2-(2-N,N-dimethylaminoethyl)- 3-indenyl]-benzyl}-pyridine of the formula stirred for an additional 15 minutes and then poured into Ice. The ether phase is washed with aqueous potassium carbonate, then with water and is dried over magnesium sulfate; the ether is evaporated under reduced pressure by keeping the temperature below 30 to yield the ditetrahydropyranyl u-benzyl-malonate. A toluene solution of this ester is gradually given to a solution of 4.86 g. of a 50% suspension of sodium hydride in mineral oil while heating and stirring for six hours. A solution of 10.8 g. of 2-N,N-dimethylaminoethyl chloride in toluene is added dropwise, and the reaction mixture is refluxed for an additional 43 hours. The toluene layer is washed with water, dried over magnesium sulfate and evaporated to yield the di-tetrahydropyranyl oc-bflnZYl-ax- (2-N,Ndimethylaminoethyl)-malonate; yield: 32.2 g. of crude material.

A mixture of the resulting di-tetrahydropyranyl 1xbenzyl-a-(2-N,N-dimethylaminoethyl)-malonate in 180 g. of polyphosphoric acid is stirred at l20 during thirty minutes, and then at during an additional twenty minutes. The reaction mixture is cooled, poured into ice-water, the acidic phase is neutralized with p0- tassium carbonate and extracted with ether. The other solution is washed with 15 percent aqueous hydrochloride acid solution, the aqueous layer is neutralized with potassium carbonate and again extracted with ether. After washing the other layer with water and drying it over magnesium sulfate, the solvent is evaporated to yield the 2-(2-N,N-dimethylaminoethyl)-indau-1-one; yield: 8 g. of crude material. The hydrochloride of the base melts at after recrystallization from a mixture of ethanol and ether.

Example 2 A solution of 5.0 g. of Z-{a-[Z-(N,N-dimethylaminoethyl)-3-indenyl]-benzyl}-pyridine in 20 ml. of ethanol is treated with 1.3 ml. of methyl iodide. During the addition, the reaction mixture is held at room temperature by cooling in water, and after ten minutes, the precipitate is filtered oil; The resulting 2{cc-[Z(2N,N-dlmethylarninoethyl) -3 -indenyl] -benzyl}-pyridine methiodide or 2-{a-[2-(2-N,N,N-trimethylammonio-ethyl)-3- indenyl]-benzyl}-pyridine iodide having the formula is purified by recrystallizing it from ethanol, M.P. 245 (decomposition) Example 3 The methiodide of Z-{a-[2-(2-N,N-dimethylaminoethyl)-3-indenyl]-benzyl}-pyridine obtained according to the procedure of Example 2 is suspended in 50* ml. of

V 1 r H "methanol. The solvent is evaporated in an open flask I while passing a stream of gaseous hydrogen chloride through the mixture. The syrupy residue is dissolved in ml. of water and concentrated aqueous ammonia is added dropwise until the pH of the solution is about 7. On cooling in the icebox, the 2-{a-[2-(2-N,N-dimethylaminoethyl)-3-indenyl]-benzyl} pyridine methochloride or 2 {u [2 (2 N,N,N trimethylammonio ethyl) S-indenyl]-benzyl}-pyridine chloride of the formula A solution of 1.2 g. of oc-[2-(2-N,N-dimethylaminoethyl)-3-indenyl]-benzyl}.-pyridine in acetone containing about 1.2 molar equivalents of gaseous methyl chloride,

is heated in a closed vessel to about 100 'for two hours. On cooling, the desired Z-{a-[2-(2-N,N-dirnethylaminoethyl)-3 indenyl]-benzyl}-pyridine methochloride or 2- {u-[2-(2-N,N,N-trimethylammonio-ethyl) 3 indenyl]- benzyl}-pyridine chloride precipitates.

A Other quaternary ammonium salts of Z-{OL-[Z-(Z-NJN- dimethylaminoethyl)-3-indenyl]-benzyl}-pyridine, such as l theethiodide, benzyl bromide, methyl nionomethyl-sulfate, methyl methane sulfonate and the like, may be prepared by reacting the free base withethyl iodide, benzyl bromide, dimethyl sulfate, methyl methane sulfonate and the like, respectively, according to the previously- 7 described procedure.

Example 5 'A column of 1650-g. of a chlorine anion exchange resin (Amberlite IRA-400, medium porosity, minimum capacity 1.2 meq. per ml., described in US. Patent No.

'2,591,573),'having a diameter of 83cm. and a height of 44.4 cm., is washed with 3500' ml. of methanol. A solution of 330 g. of 2-{u-[2-(2-N,N dimethylaminoeth- -yl)-3-indenyl]-benzyl}-pyridine methiodide in 26,000 ml.

of methanol is passed through the column during a period of one hour. The resin is washed with 13,000 ml. of methanol, the combined methanol solutions are concentrated to 'a total volume of 1400 ml. and stirred at room temperaturewith 33 g. of a charcoal preparation "for thirty minutes. The solid material is filtered off and washed with 200 ml. of methanol; the combined filtrate and washing is diluted with 12 ml. of distilled water and 1600 ml. of benzene and concentrated to a volume of 1600 ml. Addition of 1600 ml. of benzene and evaporation to a volume of 1600ml; is repeated twice; a solid material precipitates during the second solvent replacement. The suspension is chilled 'at 5 overnight, the solid material is collected, washed with three portions 'of 150 ml. each of cold benzene and dried at 65 under methyl ammonio-ethyl)-3-indenyl]-benzyl}-pyridinium diiodide of the formula o-omornmcmn 21 V Exam ple 7 To a solution of phenyl lithium (prepared by reacting. 1.75 g. of lithium wire and 20;0 g. of br'omobenzene in diethyl ether) is added dropwise 21.2 g. of Z-benzyl pyridine while maintaining room temperature and a} nitrogenatmosphere. After standing for 1 /2 to2 hours, the deep red mixture is cooled to 0, and a diethyl ether solution of 12.5 g. of 2-(2-N,N-di-isopropylaminoethyl)-indan-1-one is added dropwise; the reaction mixture is allowed to stand overnight at room temperature;

The lithium complex is decomposed by slowly adding water; the organic layer is separated and theaqueous sol ution is extracted with diethyl ether. The organic extracts are combined and Washed with 15 percent aqueous'hydrochloric acid; The acidic' solution is heated. on the steam bath to dehydrate any remaining Z-{d-[Z-(Z-IiN di-isopropylaminoethyl)-1-hydroxy-1-indanyl] benzyl}- pyridine, and is'then cooled and made'basicfby adding ammonium hydroxide. The organic material'is extracted benzyl}-pyridine' of the formula' reduced pressure to yield 238 g. of slightly ofi-white Z-{av [2 (2-N,N-dimethylaminoethyl) 3 indenyl]-benzyl}- pyridine methochloride or 2-{a-[2-(2-N,N,N-trimethylammonio-ethyl)-3-indenyl]-benzyl} pyridine chloride,

' M.P. 23 6237, which is identical with the compound described in Example 3. V

V Emmplli V A mixture of 0.8 g. of.Z-{oi-[2-(2-N,N-dimethylamino 7' ethyl)-indenyl]-benzyl}-pyridine and 2.5 molar'equivalents of methyl iodide is heated in a sealed tube and yields the 1 Z-{cx- [2-(2-N,N-dimethylaminoethyl) -3-indenyl] benzyl}-pyridine dimethiodide or 2-{a-[2-N,N,N-tri- 1 toluenesolution is washedwith an excess of a mixture" with diethyl ether, the organic layer is separated,,washed with water, dried; and evaporated; The unreacted start- 7 ing material is removed from the residue by distillation under reduced pressure (at 0.5 mm.), and the residual 2-{u-[2-(2-N,N-di-isopropyl-aminoethyl)' 3 -'ii1denyl]- CH C HgN (C 31174):

is converted into an acid addition salt thereof, for example, into-its hydrochloride by adding ethanolic hydrogen chloride to a' solution of the base. TheZ-{a-[2-1 (2-N,N-di-isopropyl-aminoethyl) 3 indenyl]-benzyl}-' pyridinehydrochloride hydrate melts at 140-145? after three recrystallizations from a mixture. of ethariol and diethyl ether. r V

The starting material used in the above reaction is i To a suspension of 0146 M of soprepared as follows: dium hydride in 700 ml. of toluene is added 100.0 'g.

'of diethyl a-benzylmalonate while maintaining a temperature just below. the boiling point of toluene... The reaction mixture in refluxed for two hoursand is then cooled to 40. A solution of 83.5 g. of 2-N,N-di-isopro-" V pyl-aminoethyl chloride in toluene is added dropwise, and the reaction mixture is refluxed overnight. The

of 15 percent aqueous hydrochloric acid andrice; the aqueous extracts are made basic with ammonium hydrox ide, and the organic materialfis'extracted with diethyl ether.' The organic layer is washed with waten dried over sodium sulfate and evaporated to dryness to yield 157.3 g. of the crude diethyl a-benzyl-a-(2-N,N-di-isopropylaminoethyD-malonate. l f t The above crude diethyl a-benzyl-a-(2-N,N-di-isopropylaminoethyD-malonate is refluxed for four hours in a mixture of 400 ml. of ethanol and 76 g. of potassium hydroxide inml; of Water. The solution is then evaporated to dryness, the residue is taken up in a minimum amount of Water, the solution is acidified with glacial acetic acid, and the desired a-benzyl-a-(2-N,N-diisopropyl-aminoethyl) -malonic acid is filtered off, washed with ice-water and air-dried overnight, M.P. l35137; yield: 88 g. The product is heated at 150 until effervescence ceases. Neither the resulting u-(2-N,N-di-isopropyl-aminoethyl)-B-phenyl-propionic acid nor its hydrochloride are obtained in crystalline form. The oily hydrochloride, prepared by adding ethanolic hydrogen chloride to the base and a minimum amount of ethanol is collected by adding the above solution to a suspension of a diatomaceous earth preparation in diethyl ether, filtering off the mixture, and washing it with diethyl ether.

The above mixture of a-(2-N,N-di-isopropyl-aminoethyl)-,3-phenyl-propionic acid hydrochloride and the diatomaceous earth prepartion is slowly added to 400 g. of polyphosphoric acid kept at 97-105 After the addition is completed, the reaction mixture is heated to 100 105 for thirty-five minutes and is then poured onto icewater. The diatomaceous earth prepartion is filtered oil, the filtrate is made basic with solid potassium carbonate and the desired 2-(2-N,N-di-isopropyl-aminoethyl)- indan-l-one is extracted with diethyl ether and isolated by washing the organic solution with diethyl ether and evaporating it to dryness. The residue is distilled under reduced pressure; the product boils at 132l34/0.07 mm; yield: 30 g.

Example 8 A solution of 0.098 M of phenyl lithium (prepared by reacting 1.372 g. of lithium in 50 ml. of diethyl ether with 15.7 g. of bromobenzene in 50 ml. of diethyl ether) is slowly added to a solution of 16.7 g. of Z-benzylpridine in diethyl ether while stirring and maintaining an atmosphere of dry nitrogen. After standing at room tem perature, a solution of 11.0 g. of 2-(2-N,N-di-n-propylaminoethyl) -in'dan-1-one in diethyl ether is added dropwise while cooling to The reaction mixture is allowed to stand overnight at room temperature; the excess of the lithium compound is decomposed-by slowly adding water, the organic phase is separated and the aqueous layer is extracted with diethyl ether. The diethyl ether extracts are combined and washed with 115 percent hydrochloric acid; the acidic solution is heated on the steam bath for one hour to completely dehydrate any Z-{a- [2- 2-N,N-di-n-propyl-aminoethyl) -1-hydroxyl-indanyl]-henzyl}-pyridine, cooled and made basic with ammonium hydroxide. The organic material is extracted with diethyl ether, the organic solution is washed with water, dried and evaporated, and the starting material is separated from the product by distillation under reduced pressure. The residue, representing the 2{0:[2(2-N,N

di-n-propyl-aminoethyl)-3-indenyl] benzyl} pyridine of the formula is converted into an acid addition salt thereof, for example, into its hydrochloride by adding an ethanol solution of hydrogen chloride to a solution of the free base and precipitating the salt by adding diethyl ether; the oily product slowly crystallizes on standing at room temperature, is treated with acetone and the Z-{IX-[2"(2N,Ndin-propyl-aminoethyl)-3-indenyl] -benzyl}-pyridine hydrochloride dihydrate melts at 132-135 after recrystallization from a mixture of ethanol and diethyl ether.

[Ind

The starting material used in the above reaction is prepared as follows: A solution of 303 g. of di-n-propylamine in 440 ml. of water is cooled to room'temperature and treated with 70.0 g. of sodium hydroxide. The temperature is adjusted to 40 and 130 g. of ethylene chlorohydrin is added. The reaction mixture is stirred for two hours, allowed to stand overnight and treated with 100.0 g. of sodium hydroxide. The organic layer is separated, dried and distilled to yield the N-(2-hydroxyethyl)-N,N- di-n-proPyLamine, BI. 18 mm.

.To a stirred solution of 105.0 g. of thionyl chloride in 176 ml. of benzene is cautiously added 102.0 g. of N-(Z-hydroxyethyl)-N,N-di-n-propyl-amine; the reaction mixture is refluxed for two hours, then allowed to stand at room temperature overnight, and the resulting precipitate is filtered oil and washed with diethyl ether. The filtrate is concentrated to yield a second crop of crystalline material. The two crops are combined to give the 2 N,N-di-n-propyl aminoethyl chloride hydrochloride which is recrystallized from a mixture of ethanol and diethyl ether, and converted into the free base by treatment with ammonium hydroxide.

To a solution of 8.70 g. of diethyl asbenzyl-malonate in 800 ml. of toluene is added 19.2 g. of a 50 per cent suspension of sodium hydride in mineral oil; after completion of the salt-formation, the reaction mixture is treated with 60.5 g. of 2-N,N-di-n-propyl-aminoethyl chloride, and Worked up as shown in Example 7; the diethyl d benzyl a-(Z-NN-di-n propyl-aminoethyl)-malonate hydrochloride, prepared for identification, melts at 80'S2.

A mixture of 1 1 *r g. of diethyl a-benzyl-cr-(2N,N-'din-propyl-aminoethyl)-malonate and 40.5 g. of potassium hydroxide in 32 ml. of water and 128 ml. of ethanol is refluxed for four hours to yield 57 g. of cz-bfil'lZYl-cz-(Z- N,N-di-n-propyl-aminoethyl)-malonic acid after being worked up as shown in Example 7. The dicarboxylic acid is then decarboxylated by heating to 180; the resulting Lit-(2 N,N-di-n-propyl-arninoethyl)-fi-phenyl-propionic acid does not crystallize, but is converted into its hydrochloride by adding ethanolic hydrogen chloride and pouring the solution into a suspension of a diatomaceous earth preparation in diethyl ether. The resulting solid material is filtered oil, washed with diethyl ether, given to 300 g. of polyphosphoric acid at -97 and heated at l00-lsl0 for thirty minutes. The reaction mixture is worked up as described in Example 7 and yields 211.2 g. of the 2-(2 N ,N di n-propyl aminoethyl)-1-one, BF. 165/ 0.7 mm.

Example 9 To a solution of phenyl lithium (prepared from 1.75 g. of lithium wire and 20.0 g. of bromobenzene in diethyl ether) is added 21.2 g. of Z-benZyl-pyridine, and the resulting lithium salt is reacted with 12.5 g. of 2-(2N,N- diethylaminoethyl)-indan-l-oue; the reaction is carried out as described in Example 7 and yields the 2-{a-[2- (2-N,N-diethylaminoethyl)-3-indenyl]-henzyl} pyridine of the formula which boils at 202/0.2 mm.

The starting material used in the above reaction may be prepared as follows: To a warm suspension of 22 g.

of sodium hydride in 1,000 ml. of toluene is given dropwise While stirring g. of diethyl cz-benzyl-ma-lonate.

. .1 The'reaction mixture'is' refluxed for onehour after completion of the addition,'then a solution of 701 g. of 2:N,N-

sure to yield 136 g. of diethyl'a-benzyl-u-(2-N,N-di

ethylaminoethyl)-rnalonate, the oxalate ofwvhich'melts A mixture of 136 g. of are a-benzyl-ccafl-Nl -di ethylaminoethylI-malonate, 65. 5 g; of potassium hydroxdie, 85 ml. ofwater and 340 m1. of ethanolisrefluxed for 4 hours, then concentrated under reduced pressure, The

solid residue is dissolved in a minimum amount of water,

. the aqueous' solution is neutralized with acetic acid while externally cooling and the resulting 'a-benzyla-('2-'N,N-

, diethylaminoethyD-malonic acid is filtered off and washed with ice M73161" and ethanol; After drying under reduced pressure,'it melts at 128; yield: 103 g. i

103 V g. of u-benzyl-u-(2,N,N-diethylaminoethyl)'-mal onic acid is heated to 180 with occasional stirring until foaming ceases; the decarbozrylation is complete after approximately 15 minutes. anddilutedwith about 15 .ml. of ethanol, ether is added and the '2-benzyl-4 N,N-diethylarnino-butyric acid crystallizes, M.P. 102-104; yield: .83 g.

83 g. of 2-benzyl-4-N,N-diethylamino-butyric acid is added to 415 g of polyphosphoric acid, kept at 100-120. The temperature is then raised to l40145 for. about 20 minutes and the acid is decomposed by pouring the reaction rnixture'into ice water and neutralizing the aqueous solution with potassium carbonate. The 2(2-N,N-di ethylarninoethyl)-indan--1 one isleirtracted with ether, the ether solution is washed'and dried, and the ether is evaporated. The. hydrochloride salt, prepared according to the previously-given procedure, melts at 164-166"; yield:

. Example 10 The Z-{u-['2-( 2-N,N-diethylamirroethyl) 3 inclenyl] benzyl}-pyridine methiodide is prepared by'dissolvingthe Z-{u-[2-(2-N,N-diethylaminoethyl)-3-indenyl] ben2yl} 7 pyridine in a small'amount of acetone and adding a slight excess of methyl iodide; itseparates from the solution, is

,filtered ofi and recrystallized -fromtethanol, M.P. 170.-

Other compounds, such as, for example Z-{oc- [2-(2-N,N- dimethylamino-2-methyl-ethyl) 3 indenyl] benzyl} pyridine, 2-{a-[2-(3-N,N-diethyalminopropyl)- 3 -..in- 'denyH-benzyl} pyridine, Z-{d-[2-(2-N,N diethylaminoethyl) =3-indenyl] -a-phenyl-et-hyl}-pyridine, 2-{a-{2- [2( laminoethyl)-3-indenyl] benzyl} pyridine," 2-{01-[2-(2- N,N-di-isopropyl-aminoethyl) 6 trifluoromethyl-in- {a- [2 (2 N,N-dimethylaminoethyl 3 -indeny1] 4benzyl}- ethyl) 33- inderiyl1-l1-phenylethyl} pyridine, Z-{iz-[Q-(Z- 'N,N-d'i-n-propyl faminoethyl)- l-methyl-3-indenyl] berrzyl}-pyri'dine and the like, the acid addition salts or the 3 quaternary ammonium derivatives thereoh esp'ecially the lower allryl quaternary ammonium halides, sulfates or tsul- The resulting melt. is cooled fonates, such as the 2-{a-[242N,N-diamaminoe h i g3, indenyl] benz'yl} pyridinje met-hoch'loride, '2-{a-[Q-(Q-N,N dimethylaminoQamethyl-ethyl) -3 -indeny-l] {benzyl} pyridine ethiodide, 2-{06-[2 -"(3 N,N-diethylan1inopropyl)-3- 5 indenyl] benzyl}-pyridine methobromide,

chloride, Z-{oc- [Q- (2-N,N-die thylaminoethyl) -6-methoxy- 3-indenyl] -bcnzyl}-pyridine methiodide, Z-{oc-[G acctyl-Z- 1 (2-N,N dimethylaminol-methyl-ethyl) -3-indei1Yl1-bnzyl}-pyridine methobromide, Z-{a- [6-N,N-dimethylamino 2 (2-N-ethyl N methyl-aminioethyl) 3 a indenyl1- bnzyl}-pyridine methochloride, 2-{d-[2-(2-N,N-dim'ethyl-' amirioethyl)3-indenyl]-3-rnethyl-benzyl}rpyridine' ethochloride, 4-{u- [2-(2 N ,N dimethylaminoethyly- 3 in:

like, are prepared according to the above-described pro- 1 'cedure. The quaternary ammonium derivatives are obtained by reacting the free bases with an appropriate reactive ester, such as a lower alkyl halide, adi-lower alkylsulfate, a lower alkyl organic sul fonate and the like, and, if desired, ,may be converted into other quaternary amm'oniumt compounds according to the procedures de- 7 in which A is lower alkylene, Am stands :for :a member selected from the group consisting of N,N-di-lower alkylamino, N-cycloalky-l-N-lower alkyl-arnino, in which cycloalkyl has from five to seven ring carbonxatoms, N-lower al-kyl-N-phenyl-lower alkyl-amino, -lN,N-,a1kylene imino, in whichja'lkylene has from four to six carbon atoms, 4- morpholino and 4-lower alkyll-piperaz-ino, R is a mem-' ber selected from the group consisting of hydrogen, lower -alkyl, trifluoromethyl, lower alkoxy, halogeno, lowerl alkanoyl and N,N-di-lower alkyl-arnino, R stands for a member selected from the group consisting of hydrogen and lower alkyl,.and Ph stands for a-member selected from the group consisting of phenyl, (lower alkyly-uhen- -yl, '(l'ower alkoxy)'-phenyl', i(halogeno)-.pheny1 and (th- "-fluorornethynqphenyl, and. pharmaceutically acceptable 7 acid addition salts thereof. t

2.. The member-selected from the group consisting of -the lowerlalkylfquatrnary ammonium halides, the lower a1kyl quaternary ammonium sulfates, \the flow'e'r. alkyl quaternary ammonium su'lionates, the phenyl-loweralkyl quaternary ammonium halides, the phenyl-lower .alkyl 7 5 quaternary ammonium'sul-fates, the phenyl-lowcr' alkyl denyl]-benzyl}-pyridine dimethiodide, 4-{a-3,4-dichloroquaternary ammonium sulfonates of a compound of the formula C\\ R1 I C-A-Am CIHI 10 in which A is lower alkylene, Am stands for a member selected from the group consisting of N,N-di-l-ower alkylamino, N-cycloalkyl-N-lower alkyl-am-ino, in which cycloalkyl has from five to seven ring carbon atoms, N-lower aJkyl-N-phenyl-lower alkyl-amino, 1-N,N-a1kylene-imino, in which alkylene has from four to six carbon atoms, 4- morpholino and 4-lower alkyl-l-piperazino, R is a member selected from the group consisting of hydrogen, lower alkyl, trifluoromethyl, lower alkoxy, halogeno, lower alkanoyl and N,N-di-lower alkyl-amino, R is a member selected from the group consisting of hydrogen and lower alkyl, and Ph' stands for a member selected vfrom the group consisting of phenyl, (lower alkyl)-phenyl, (lower alkoxy)phenyl, (halogeno)-phenyl and (trifluoromet-hyl)-phenyl.

3. A compound of the formula.

in which A is lower alkylcne having from two to three carbon atoms, and Am stands for N,N-di-lower alkylamino.

4. Pharmaceutically acceptable acid addition salts of a compound of the formula 18 :in which A is lower alkylene having from two to three carbon atoms, and Am stands for N,N-di-llower alkylamino.

5. The lower alkyl quaternary ammonium halides of a compound of the formula in which A is lower alkylene having from two to three carbon atoms, and Am stands for N,N-di-lower alkylamino.

6. 2 {a [2 (2 N,N dimethylaminoethyl) 3- indenyl] -.benzyl}-pyridine.

7. The lower alkyl quaternary ammonium halides of 2 {a [2 N,N-dimethylaminoethyl) -3 indeny1]-henzyl}-pyridine.

8. The 2 {u [2 (2 N,N dimethylaminoethyD- Z-indenyl] -benzyl}-pyridine methoch-loride.

9. The 2 {a [2 (2 N,N dimethylaminoethyl)- 3-indeuyl] -oenzyl}-pyridine methiodide.

10. 2 {on [2 (2 I,N diethylaminoethyl) 3- indenyl] -b enzyl} -pyridine.

1 1. 2 {a [2 (2 N,N di 11 propyl aminoethyl)-3-indenyl]benzyl}-pyridine.

12. 'Pharmaceutically acceptable acid addition salts of 2 {a [2 (2 N,N di n propyl aminoethyl) 3- indenyl] -henzyl}-pyridiue.

13. 2 {a [2 (2 N,N-di-isopropyl aminoethyl)- 3-indenyl1-henzyl}pyridine.

14. Pharmaceutically acceptable acid addition salts of 2 {a [2 (2 N,N di iso propyl aminoethyl)- 3 -indenyl] -b enzyl} -pyridine.

No references cited.

IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non 3,189,612 June 15, 1965 Charles Ferdinand Huebner It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 18, line 26, for "[2N,N" read [2-(2N,N-

Signed and sealed this 5th day of April 1966.

(SEAIJ Attest:

ERBEST WZSWUDEB. EDWWMRD l BREDDHHl Attesting Officer Commissioner of Patents 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 3. A COMPOUND OF THE FORMULA 